The heart . . is the beginning of life; the sun of the microcosm . . for it is the heart by whose virtue and pulse the blood is moved, perfected, made apt to nourish, and is preserved from corruption and coagulation; it is the household divinity which, discharging its function, nourishes, cherishes, quickens the whole body, and is indeed the foundation of life, the source of all action.—William Harvey, 16281

The history and our still emerging understanding of the heart are a remarkable story, with origins in antiquity, centered initially on clinical observations. Thought at one time to be the center of the soul and impervious to disease, the heart was long a source of mystery and wonder, studied in science and fascinated about in literature and the arts. Most historians agree that William Harvey’s discovery of the circulation of blood in the early 17th century is a good place to start the modern history of cardiovascular medicine. Following Harvey, cardiology has pursued a pathway of descriptive anatomy and pathology in the 17th and 18th centuries, auscultation and its correlations in the 19th century, an understanding of cardiac disease and its pathophysiology in the second half of the 19th and first half of the 20th centuries, and major advances in the diagnosis and treatment of heart disease from there into the 21st century.2-5 What has emerged in the 21st century is a medical specialty with incredible tools of diagnosis including blood biomarkers and multiple imaging modalities; numerous medical treatment options that include drugs, biologics, and devices; and surgical options involving complex operations that both repair and replace dysfunctional anatomy.

The introduction of the first instruments of precision—blood pressure measurement, the chest x-ray, and the electrocardiogram—in the 1890s and early 20th century, led to the creation of the specialty of cardiology. Since the 1950s, following the advent of cardiac catheterization and surgery, cardiology has evolved into multiple, highly specialized disciplines focusing on coronary artery disease, heart failure, arrhythmias, imaging, and preventive care. Early diagnosis of cardiac risk, aggressive medical treatment of cardiac diseases coupled with increasing attention to prevention have led to a gradual decrease in mortality for cardiac disease.6 A hallmark of cardiovascular medicine in the early 21st century has been its emergence at the forefront of the evidence-based medicine movement with an intense commitment to quality care7-9 through continuous investigation and incorporation of new knowledge into clinical practice guidelines by the major professional societies and public health organizations.10,11

Many of the initial key discoveries are now recalled as eponyms attached to diseases or physical signs. As the number of investigators has grown exponentially and internationally, it is increasingly difficult to assign singular credit to contributions for which many are ultimately responsible. Taking all of these considerations into account, we have chosen to provide a condensed narrative by subject, selectively highlighting important events and key figures in the grand story of cardiovascular medicine written by our illustrious predecessors.1-5,12-18

Early civilizations considered the heart to be a source of heat and believed that the blood vessels carried pneuma, the life-sustaining spirit of the vital organs. This concept was most fully elaborated by Claudius Galen (AD 130-200), whose erroneous teachings were entrenched for 1300 years, until Andreas Vesalius corrected his anatomy (1543), and William Harvey proposed that blood circulates because of the force of the heart (1616).2,3

Harvey’s discovery of the circulation of blood (Fig. 1–1) is considered to mark the beginning of modern cardiology as well as the introduction of experimental observation. Starting in 1603, Harvey dissected the anatomy and observed the motion of the cardiac chambers and flow of blood in more than 80 species of animals. His experimental questions “to seek unbiased truth” can be summarized as follows: what is the relationship of the motion of the auricle to the ventricle? Which is the systolic and which is the diastolic motion of the heart? Do the arteries distend because of the propulsive force of the heart? What purpose is served by the orientation of the cardiac and venous valves? How does blood travel from the right ventricle to the left side of the heart? Which direction does the blood flow in the veins and the arteries? How much blood is present and how long does its passage take?

After many experiments and without knowledge of the capillary circulation of the lungs, which was not known until 1661, Harvey stated: “It must of necessity be concluded that the blood is driven into a round by a circular motion and that it moves perpetually; and hence does arise the action or function of the heart, which by pulsation it performs.” This was published in 1628 as Exercitatio Anatomica de Motu Cordis et Sanguinis in Animalibus.1 This revolutionary concept eventually became accepted in Harvey’s lifetime and remains the foundation of our understanding of the purpose of the heart.

The Arterial Pulse

Until the 17th century, the clinical examination consisted of palpating the pulse and inspecting the urine to reveal disease and predict prognosis. In Chinese acupuncture, the pulse was timed according to the physician’s respiration whereas digital pressure was applied to elicit information. Galen wrote 18 books on the arterial pulse in the 2nd century, providing elaborate descriptions that influenced clinical practice well into the 18th century.2,3 The 1-minute pulse watch, invented by Floyer in 1707, offered the first opportunity to measure the heart rate accurately; however, this did not become a routine part of medical practice until the mid 19th century.3 Since the 19th-century observations of Dominic Corrigan, the carotid arterial pulse has been linked to aortic valve disease and is essential for timing systole at the bedside. In 1847, Carl Ludwig in Leipzig invented the kymograph, a pulse writer that would elevate physiology to a new level and be used to inscribe arterial and venous pulses. Pulsus alternans was described by Ludwig Traube in 1872, and Adolf Kussmaul called attention to the paradoxical pulse in 1873, noting that the arterial pulse could transiently disappear on inspiration even though the heart sounds were still audible. Before electrocardiography, arterial pulse recordings were applied to diagnose arrhythmias, as shown by James Mackenzie in The Study of the Pulse (1902).19

Percussion

In 1761, Leopold Auenbrugger, a Viennese physician, published a book proposing “percussion of the human thorax, whereby, according to the character of the particular sounds thence elicited, an opinion is formed of the internal state of that cavity.”2 He had observed his father, an innkeeper, use this technique to check the wine levels in his casks. Percussion was reintroduced by Jean-Nicolas Corvisart in early 19th-century France and became an essential addition to the chest examination until it was mostly supplanted by the chest x-ray.

The Jugular Venous Pulse

Jugular venous wave recording was initiated in mid-19th-century France by Pierre-Carl Potain. In the 1870s, Mackenzie sought to interpret arrhythmias by understanding arterial and venous pulse waves. Using a kymograph, then an ink-writing polygraph, Mackenzie applied his intuitive skills to the interpretation of jugular waves, which he labeled “a, c, and v.”20 Thomas Lewis, a disciple of Mackenzie, described the technique of bedside assessment of jugular venous pressure relative to the sternal angle in 1930.

Auscultation

Auscultation of the chest was first practiced by Hippocrates (BC 460-370), who applied his ear directly to the chest. The invention of the wooden monaural stethoscope (Greek: stethos, chest; skopein, to view or to see) by René Laennec in Paris (1816) introduced a powerful, although initially difficult, technique to listen to cardiovascular sound.21,22 This method spread to Europe and Great Britain—where it was promoted by Skoda, Stokes, Hope, Williams, and others—and to America, where Austin Flint became its champion. By the mid 19th century, the stethoscope was established as an indispensable tool for the examination of the heart and lungs. Diagnoses based on percussion and auscultation were subjected to the critical analysis of the autopsy by Corvisart, Laennec, Rokitansky, and Skoda, and murmurs were assigned according to their underlying pathology. Symptoms not supported by auscultatory or autopsy findings were often thought to be functional or unreliable. The stethoscope evolved from a monaural to a binaural device in 1855, and separate heads were developed by Bowles (1894) and Sprague (1926). Grading of systolic murmurs was introduced by Samuel Levine in 1933. The acoustic principles of cardiovascular sound became better understood through the work of Rappaport and Sprague (1940s); and correlations were made with phonocardiography and cardiac catheterization by Paul Wood, Aubrey Leatham, Samuel Levine, and others between 1950 and 1975. In 1961, physiologist Robert Rushmer proposed the acceleration-deceleration theory that remains the concept of the generation of normal and abnormal heart sounds. Auscultation continues to be valuable although less relied on today as imaging tools such as the cardiac echocardiogram make visualization of cardiac structures straightforward, reproducible, and reliable.

The Electrocardiogram

In 1856, von Kölliker and Müller demonstrated that the heart also produced electricity. Augustus Waller, with a capillary electrometer device (1887), detected cardiac electricity from the limbs, a crude recording that he called an “electrogram.” Willem Einthoven, a physiologist in Utrecht, devised a more sensitive string galvanometer (1902), for which he received the Nobel Prize, and the modern electrocardiogram was born. Initially weighing 600 lb and requiring five people to operate, the 3-lead electrocardiograph would eventually become portable, 12 leads, routine, and capable of providing both static and continuous recordings of cardiac rhythm (Table 1–1).23

Nineteenth century researchers debated whether the heartbeat was stimulated by the heart muscle or was caused by external nervous or local ganglionic control—the myogenic versus the neurogenic theory. The answer was finally provided by the anatomic discovery and descriptions of the electrical system of the heart: the Purkinje fibers (1839), bundle of His (1893), bundle branches (1904), atrioventricular (AV) node (1906), and sinus node (1907).24 With the electrocardiogram, the activation and sequence of stimulation of the human heart could now be measured, and the anatomic basis for the conduction system confirmed. Thomas Lewis in London was the first to realize its great potential, beginning in 1909, and his books on disorders of the heartbeat became essential for aspiring electrocardiographers.2,16 Disorders of the heartbeat and abnormalities in the activation of the human heart, heretofore unknown or inferred from pulse tracings or experimental observations, became new clinical currency; palpitations became premature atrial or ventricular beats, and tachycardias and atrioventricular block could be understood. When electrocardiography was added to the chest x-ray and cardiac fluoroscopy in the early 20th century, clinical cardiology became a field of its own, inextricably linked to technology, a trend that continues in the 21st century. Those who interpreted the complicated tracings, known as cardiologists, became practitioners of this new specialty.17 By the 1930s, the electrocardiogram had become 12 leads and a necessary confirmation for myocardial ischemia or infarction. When electrocardiography was combined with the Master “2-step” exercise test (1940s), bicycle and treadmill stress testing (1960s), and nuclear and echocardiography imaging (1970s), a superior diagnostic approach to patients with chest pain became available. Continuous bedside monitoring (Paul Zoll, 1956) and the ambulatory detection of arrhythmias (Holter, 1961) became commonplace in the 1960s; and implanted loop recording appeared in 1999.

Pacing the heart in cardiac standstill was first carried out by John MacWilliam in Aberdeen in 1887. Experiments with external pacemakers in the 1920s to 1930s by Mark Lidwill in Australia and Albert Hyman in the United States showed their feasibility. A temporary pacemaker was inserted in 1952 by Zoll, and an internal pacemaker was inserted in a human by William Chardack in 1960.25 Although initially plagued by faulty operation, lead breakage, infection, and early battery failure, pacemakers eventually became a marvel of reliability, complexity, and durability. Progressive advances include transvenous leads (1965), lithium iodine batteries (1972), multiprogrammability (1972), dual chamber pacing (1980), rate adaptive modes, and antitachycardia programs. Biventricular pacing (1998) for patients with left ventricular dysfunction coupled with defibrillation capability has improved the quality of life and reduced mortality among some groups of patients with systolic heart failure.26

Electrophysiologic testing in humans began as an offshoot of basic catheterization laboratory investigations in the early pacemaker era. Intracardiac potentials were first measured in 1945. Catheter techniques were used to localize the His bundle (Scherlag and Damato, 1967) and to identify accessory pathways (Jackman, 1983). Programmed electrical stimulation of the heart was introduced to localize, provoke, and terminate arrhythmias (Durrer, Wellens, and Coumel, 1967). Mapping techniques, applied to the surface of the heart for the localization and resection of accessory pathways (1968) and the surgical ablation of ventricular arrhythmias (1974) and atrial fibrillation (1991), became an essential method of investigation. As catheter methods of ablation improved, first coupled with intracardiac high-energy shock of the atrioventricular node (1982) and then with radio-frequency current (1987), ablation moved from the surgery suite into the laboratory setting, populated by a new subspecialty group—the electrophysiologists. Catheter ablation of AV nodal reentry was the next great success story. Atrial flutter and fibrillation and ventricular tachycardia are the newest targets for catheter ablation as the understanding of arrhythmias evolves through the use of more sophisticated intra-cardiac electrocardiograms coupled with a more detailed correlation with anatomy using MRI and CT imaging to help guide procedures.27,28 Through an understanding of the mechanisms of arrhythmias and the identification of genes encoding cardiac ion channels—especially the long-QT and Brugada syndromes—electrocardiography has reemerged as a critical diagnostic and investigative tool.29-31

The Cardiac Catheter

If the ability to measure cardiac rhythm using the electrocardiograph was a touchstone for the identification of the cardiologist at the dawn of the 20th century, it was the ability to invasively measure cardiac pressures and oxygen saturation as well as the imaging of cardiac structures using the cardiac catheter that marked the transition to the modern definition of the cardiovascular specialist. Many of the fundamentals of modern cardiovascular instrumentation and physiology originated in mid-19th-century France. Claude Bernard in 1844 was the first to insert a catheter into the heart of animals to measure temperature and pressure.2 In the 1860s, Etienne Jules Marey combined the kymographic instrumentation created by Ludwig in Leipzig in 1847 with an air-filled manometer for the graphic registration of biological phenomena.12 Marey’s pulse writer—the sphygmograph—was used for recording the external pulsation of the heart and arteries and was a prototype for noninvasive devices in cardiology. In the early 1860s, Auguste Chauveau, a veterinary physiologist, and Marey collaborated to develop a system of devices called sounds, forerunners of the modern cardiac catheter, which they used to catheterize the right heart and left ventricle of the horse.12 They recorded values of intracardiac pressure with superb tracings and correlated the intracardiac events with precision to show the relation of atrial and ventricular systole to the apex impulse. In 1870, Adolph Fick provided his oximetric formula to measure cardiac output.

Cardiac catheterization in humans was thought an inconceivable risk until Werner Forssmann, a 29-year-old surgical resident in Germany, performed a self-catheterization in 1929.32,33 Interested in discovering a method of injecting adrenaline to treat cardiac arrest, Forssmann passed a ureteral catheter into his antecubital vein and confirmed its right atrial position using x-ray. The next year he attempted to image his heart using an iodide injection. However, he was reprimanded by superiors and did not experiment further. Catheterization began in earnest in the early 1940s in New York and London. André Cournand and Dickinson Richards at Bellevue, interested in respiratory physiology, developed and demonstrated the safety of complete right heart catheterization, for which they shared the Nobel Prize with Forssmann in 1956.12,15

The cardiac catheter was viewed initially as an instrument to measure pressure and cardiac output, sample blood contents, or deliver contrast agents for cardiovascular angiography. Brannon and Warren in Atlanta were the first to apply the catheter to diagnose heart disease—an atrial septal defect—in 1945. It was the impetus of cardiac surgery requiring an accurate diagnosis, initially for congenital heart and rheumatic mitral disease, that brought cardiac catheterization out of the physiology laboratory and to the forefront of clinical cardiology in the 1950s. Improved catheters and pressure manometers, automatic film changers, and the introduction of retrograde left heart catheterization by Henry Zimmerman (1950) and a percutaneous approach by Sven Seldinger (1953) advanced the technique, accompanying heart surgery into the era of valve replacement in the 1960s. Mason Sones’s accidental injection of contrast directly into a right coronary artery (1958) was a serendipitous leap forward, demonstrating that the epicardial coronary arteries could be safely visualized using percutaneous techniques. The Judkin transfemoral approach (1967) simplified selective coronary catheterization. Visualization of the coronary circulation ultimately led to the introduction of coronary bypass surgery by René Favoloro (1967) and percutaneous transluminal coronary angioplasty (PTCA) by Andreas Grüntzig (1977).33,34 Since then, the versatile cardiac catheter has continued to evolve, carrying delivery systems or instruments ranging from ultrasound, balloons, and stents to defibrillators (Table 1–2; see also Table 1–1). The modern descendant of Forssmann and others is now an endovascular specialist, capable of both diagnosing and treating diseases of cardiac structure and function as well as increasingly involving diseases of the peripheral arterial and venous circulations.35

Imaging of the Heart

Radiography

Modern imaging technology began with Konrad Roentgen’s discovery of x-rays in 1895, for which he was awarded the Nobel Prize in Physics in 1901.36,37 Within a year, fluorescent screens were available to view cardiac pulsations. Contrast agents incorporating sodium iodide were necessary to visualize the organ cavities. Moniz in Lisbon (1931) and Castellanos in Cuba (1937) were the first to image the interior of the heart with intravenous angiograms.2 In the mid 20th century, electronic x-ray technology with the image intensifier allowed enhanced viewing of dynamic events in real time (see Table 1–1). Angiography became the essence of cardiovascular imaging for several decades after the mid 20th century, vital to the diagnosis and management of coronary disease during the 1960s, and it continues to play a central role.

Nuclear Cardiology

Nuclear cardiology began with Herrman Blumgart, who injected radon to measure the circulation time in 1927; followed by G. Liljestrand, who determined normal blood volume in 1939; and Myron Prinzmetal, who monitored the transit of radiolabeled albumin through the heart in 1948.12,38 Following World War II, radioactive isotopes and scintillation cameras became available for imaging purposes. The gamma camera of Hal Anger, a key development introduced in 1952, provided a high-resolution scanning capability that could visualize the cardiac chambers and assess function and shunting without moving the patient. Electrocardiographic gating, starting in the early 1970s, greatly improved the analysis of wall motion and ejection fraction, as did single-photon emission computed tomography (SPECT) in the 1990s. Nuclear stress testing for ischemia was introduced by Zaret and Strauss in 1973 using potassium 43 as the tracer. Redistribution studies, taking advantage of the properties of thallium 201 and technetium 99m, have improved the performance of the test, and pharmacologic stress testing has expanded their use.12,38 Advances combining positron emission tomography (PET) or SPECT scanning with CT allow the integration of knowledge of anatomy with cardiac function. Imaging of “vulnerable” atherosclerotic plaque that would allow detection of patients at risk for acute ischemic events remains a laudable but elusive diagnostic goal.39

Echocardiography

Ultrasound imaging dates back to the production of sound waves from piezoelectric crystals in 1880 and the military use of sonar for the detection of reflected sound waves during World War II.12 Cardiac ultrasound was introduced in Sweden by Inge Edler and Helmuth Hertz, who detected the anterior mitral leaflet with postmortem correlation—an ice pick through the chest into the mitral leaflet (1954). Starting in the mid 1960s with the detection of pericardial effusion and left ventricular size, M-mode echocardiography became a powerful clinical technique developed by Harvey Feigenbaum who taught the first generation of echocardiographers. Contrast echocardiography (1969), two-dimensional echocardiography (1974), pulsed Doppler hemodynamics (1975), stress echocardiography (1979), Doppler color-flow (1982), and transesophageal imaging (1985) have added to its enormous success. Intraoperative transesophageal monitoring and the intrauterine diagnosis of congenital heart disease have become possible. New additions include the assessment of diastolic function and tissue strain rate and three-dimensional capabilities. Digital recording has significantly transformed the acquisition, storage, and interpretation of studies. Echocardiography has safely and brilliantly illuminated the heart and its function, becoming the main imaging tool of choice given its ready availability, its ease of use, and extensive investigations supporting its use as a diagnostic tool.36,37,40,41

Computerized Tomography and Magnetic Resonance Imaging

The 3 decades following the introduction of the gamma camera and ultrasound brought unbelievable expansion to the medical imaging field, including CT (1963-1971), SPECT (1963-1981), PET (1975-1987), and MRI (1972-1981), each delivering its own exciting ability to look at the structure and/or function of the heart in a different way (see Table 1–1). Each of these imaging techniques has spawned new clinical disciplines in cardiology and radiology that continue to the present. Electron-beam computed tomography (EBCT), introduced in 1990, has been used to detect early coronary atherosclerosis. The multi-slice CT angiogram (2005) now provides detailed coronary anatomy along with ventricular wall motion.42 With the possibility of perfusion scanning being added to CT capabilities, CT is competing with coronary angiography and nuclear imaging as the initial imaging study for patients with suspected coronary artery disease, although concerns have arisen recently about the cumulative effects of radiation exposure that accompanies cardiac imaging.43,44

Cardiac magnetic resonance imaging has emerged as a powerful tool to visualize cardiac structures with incredible clarity and precision.45 For example, MRI can be useful in the very accurate quantification of myocardial infarct size that correlates well with pathologic examination.46 Because MRI does not involve ionizing radiation, it has emerged as a very helpful imaging modality in the sequential care of children and adults with complex congenital heart disease, including to follow up and plan for percutaneous and surgical repairs. MRI techniques can be used for perfusion scanning using vasodilating stress agents.47,48 Finally, MR angiography (MRA) now allows contrast-enhanced imaging of vascular structures that often can provide the endovascular specialist with a “roadmap” for therapeutic interventions. As with cardiac catheterization and angiography, collaborations among academics, clinicians and industry, leveraging the advantage of the information processing capabilities of the computer, have provided the basis for each technological advance.

Diagnosis of Coronary Artery Disease and Its Etiology